The major objective of this research program is to gain new insights into the molecular and cell biological mechanisms underlying the production and actions of insulin and related peptide hormones of the islets of Langerhans, including their genetic basis, evolutionary origins, and disorders in these processes which may contribute to the pathophysiology of diabetes and/or other diseases. New projects and extensions of previous work are proposed as follows: 1) Studies on prohormone convertases PC2 (SPC2) and PC3 (SPC3), including their biosynthesis, maturation and actions on prohormone processing in mice with targeted disruptions in their genes; 2) Effects of the SPC2 gene null mutation on the development and morphology of the islets of Langerhans; 3) studies on the regulation and tissue-specific transcription of the genes encoding SPC2 and SPC3; 4) Studies on the structure and functional significance of conserved subdomains of the convertases; 5) Studies on the processing of ProIGF-I and its significance in normal and transformed cell lines; 6) Studies on the effects of carboxypeptidase E (CPE) deficiency on islet prohormone processing; 7) Studies on the insulin receptor with emphasis on the binding ectodomain, and the use of receptor fusion proteins for studies of its structure and biosynthesis; 8) Further studies on the evolution of insulin and the IGFs and their receptor proteins in lower vertebrates, with emphasis on the divergence of metabolic and growth regulatory functions of a common ancestral insulin-like peptide (ILP) in protochordates.